Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid

Note added in July 2014: Since the original version of this review, guidance around LABA has changed. International asthma guidelines now only recommend the use of LABA in conjunction with ICS. The US Food and Drug Agency (FDA) has issued a warning that LABA should not be used to treat asthma without concurrent ICS. The review will continue to be available for people to read on the Cochrane Library, but we will not update the review again. It is no longer considered safe to take LABA on their own without taking inhaled steroids due to harms which can occur.

Plain language summary published in 2006: In this review of studies in which patients were either not on inhaled corticosteroids, or in which some patients but not all were on inhaled corticosteroids, treatment with regular long-acting beta-2 agonists such as salmeterol (Serevent) or formoterol (Foradil, Oxis) in chronic asthma resulted in fewer asthma symptoms by day or night, less relief bronchodilator medication requirement, better lung function, a lower risk of acute worsening of asthma and better quality of life, but most of the evidence comes from groups in which at least some used inhaled corticosteroid therapy. There is less information on asthma control in patients who did not use a regular 'preventer medication' or in children under twelve years, but the same generally positive effects on symptoms and lung function seem to apply. We have also been particularly focused on serious adverse events, given previous concerns about potential risks, especially of death, from regular beta-2 agonist use. A significant increase in asthma related deaths or life threatening experiences has been found in a recently published surveillance study, with an increased risk of around one event over 6 months for every thousand patients treated. This increase was mainly in African-Americans and those not on inhaled corticosteroids, although these observations were drawn from analyses conducted after the event (post-hoc) and as such lack the validity of pre-defined distinctions.

Authors' conclusions: 

LABA are effective in the control of chronic asthma in the "real-life" subject groups included. However there are potential safety issues which call into question the safety of LABA, particularly people with asthma who are not taking ICS, and it is not clear why African-Americans were found to have significant differences in comparison to Caucasians for combined respiratory-related death and life threatening experiences, but not for asthma-related death.

Since the original version of this review, the US Food and Drug Agency (FDA) has added a warning that LABA should not be used to treat asthma without concurrent ICS. International guidelines only recommend the use of LABA in conjunction with ICS. Readers should consult the overviews which summarise the results of Cochrane reviews on the safety of LABAs in adults and children (Cates 2012; Cates 2014).

Read the full abstract...
Background: 

Asthma is a common respiratory disease among both adults and children and short acting inhaled beta-2 agonists are used widely for 'reliever' bronchodilator therapy. Long acting beta-2 agonists (LABA) were introduced as prospective 'symptom controllers' in addition to inhaled corticosteroid 'preventer' therapy (ICS).

We originally analysed studies comparing the use of LABA with placebo in mixed populations in which only some were taking ICS and in populations not using ICS therapy. However international guidelines no longer recommend the use of LABA in people who are not taking ICS for their asthma. We are therefore no longer updating this review.

Objectives: 

This review aimed to determine the benefit or detriment on the primary outcome of asthma control with the regular use of LABA compared with placebo, in mixed populations in which only some were taking ICS and in populations not using ICS therapy.

Search strategy: 

We carried out searches using the Cochrane Airways Group trial register, most recently in October 2005. We searched bibliographies of identified RCTs for additional relevant RCTs and contacted authors of identified RCTs for other published and unpublished studies.

Selection criteria: 

All randomised studies of at least four weeks duration, comparing a LABA given twice daily with a placebo, in chronic asthma. Selection criteria to this updated review have been altered to accommodate recently published Cochrane reviews on combination and addition of LABA to ICS therapy. Studies in which all individuals were uniformly taking ICS were excluded from this review.

Data collection and analysis: 

Two review authors performed data extraction and study quality assessment independently. We contacted authors of studies for missing data.

Main results: 

Sixty-seven studies (representing 68 experimental comparisons) randomising 42,333 participants met the inclusion criteria. Salmeterol was used as long-acting agent in 50 studies and formoterol fumarate in 17. The treatment period was four to nine weeks in 29 studies, and 12 to 52 weeks in 38 studies. Twenty-four studies did not permit the use of ICS, and forty permitted either inhaled corticosteroid or cromones (in three studies this was unclear). In these studies between 22% and 92% were taking ICS, with a median of 62%. There were significant advantages to LABA treatment compared to placebo for a variety of measurements of airway calibre including morning peak expiratory flow (PEF), evening PEF and FEV1. They were associated with significantly fewer symptoms, less use of rescue medication and higher quality of life scores. This was true whether patients were taking LABA in combination with ICS or not. Findings from SMART (a recently published surveillance study) indicated significant increases in asthma related deaths, respiratory related deaths and combined asthma related deaths and life threatening experiences. The absolute increase in asthma-related mortality was consistent with an increase of around one per 1250 patients treated with LABA for six months, but the confidence intervals are wide (from 700 to 10,000). Post-hoc exploratory subgroups suggested that African-Americans and those not on inhaled corticosteroids were at particular risk for the primary end-point of death or life-threatening asthma event. There was also a suggestion of an increase in exacerbation rate in children. Pharmacologically predicted side effects such as headache, throat irritation, tremor and nervousness were more frequent with LABA treatment.

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